Neuroblastomas are the most common cancer in infants, with about 700–800 diagnoses per year in the US, according to the American Cancer Society. Some of the most high-risk cases are driven by elevated expression of the protein N-Myc, a transcription factor that causes increased cell proliferation.
N-Myc is difficult to target in part because its structure is more malleable than that of a rigid protein. Additionally, it is not an enzyme—meaning it doesn’t have a predetermined pocket where a molecule is already supposed to go.
But while N-Myc is floppy in normal circumstances, it can lean on Aurora kinase A (AURKA) to provide a scaffold. At the American Chemical Society Spring 2025 meeting on Monday, Daniel Harki, Northrop Professor and Margaret Harvey Schering Land Grant Chair for Cancer Research at the University of Minnesota Twin Cities, presented how this feature could be targeted to decrease N-Myc levels.
“N-Myc has a pretty short half life, but when it binds to AURKA through protein-protein interaction, it sticks around for a while, and then as a transcription factor, it can drive all of these gene programs that cause the cell to have the properties of a cancer cell with respect to proliferation,” he said.
Harki’s lab is one of a few groups developing Aurora kinase A degraders, which eliminate this critical scaffold for N-Myc. Using a proteolysis-targeting chimera (PROTAC) system, their degraders bind to AURKA and recruit an E3 ubiquitin ligase complex. This directs AURKA to the proteasome, where proteins that aren’t needed by the cell are broken down. This research was published in Cell Chemical Biology in February and, along with some unpublished data, was discussed during a talk in the Division of Medicinal Chemistry at ACS Spring 2025 (DOI: 10.1016/j.chembiol.2024.12.006).
According to Harki, the project sprang from an unexpected finding: The team was trying to degrade another target with molecules based on ribociclib, a drug approved by the US Food and Drug Administration for breast cancer. One of their ribociclib-based degrader candidates, called HLB-0532259, didn't have a very high affinity for the group’s desired target. Instead, it had a high affinity for AURKA.
“We followed the chemistry, and that ultimately nucleated a new project in my group,” Harki said.
HLB-0532259 isn’t a perfect neuroblastoma treatment, and the group is working on optimizing its degraders to improve their solubility and degradation efficiency. Animal tests with the compound showed that while tumors were reduced, they did rebound. AURKA is also required for normal cell function, so additional safety tests will also have to be done. Finally, the Harki lab wants to learn more about how exactly these degraders are working to eventually reduce N-Myc levels.